The primary objective of this research program is the synthesis of new folate antagonists as potential antineoplastic agents. The compounds to be prepared will consist largely of quinazoline analogs of known antifols possessing significant antitumor activity. To be of clinical value the new compounds should demonstrate efficacy against tumors which are characterized by natural or acquired resistance to amethopterin. Antagonists which block folic or folinic acid uptake or which inhibit folate-dependent enzymes other than dihydrofolate reductase are of particular concern in this regard. Therefore, thymidylate synthetase will constitute a principal target for chemotherapeutic attack. The development of potent inhibitors of this enzyme which can enter cells by passive diffusion and effectively cross the blood-brain barrier could have significant clinical utility. In support of the synthetic program, enzyme inhibition studies with dihydrofolate reductase, thymidylate synthetase and 5,10- methylenetetrahydrofolate dehydrogenase will be conducted. In addition to conventional anticancer testing, target compounds will also be evaluated for their ability to be transported into L1210 leukemia cells.